Repair of Formamidopyrimidines in DNA Involves Different Glycosylases

Hu, Jingping; Souza-Pinto, Nadja C. de; Haraguchi, Kazuhiro; Hogue, Barbara A.; Jaruga, Paweł; Greenberg, Marc M.; Dizdaroğlu, Miral; Bohr, Vilhelm A.

doi:10.1074/jbc.m508772200

Cited by 181 publications

(157 citation statements)

References 41 publications

(47 reference statements)

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“…One mechanism focuses on the implications for an insufficient repair of ROS-induced DNA lesions in the mitochondria. Recently, mitochondrial localization of NEIL1 was demonstrated, thus linking NEIL1 to repair of oxidative damage in mtDNA (22). Our data demonstrate significantly elevated levels of mtDNA damage and deletions, suggesting that at least a subset of lesions may not be repaired in the mtDNA genome.…”

Section: Discussionmentioning

confidence: 62%

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The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase

Vartanian

Lowell

Minko

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

224

221

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Endogenously formed reactive oxygen species continuously damage cellular constituents including DNA. These challenges, coupled with exogenous exposure to agents that generate reactive oxygen species, are both associated with normal aging processes and linked to cardiovascular disease, cancer, cataract formation, and fatty liver disease. Although not all of these diseases have been definitively shown to originate from mutations in nuclear DNA or mitochondrial DNA, repair of oxidized, saturated, and ring-fragmented bases via the base excision repair pathway is known to be critical for maintaining genomic stability. One enzyme that initiates base excision repair of ring-fragmented purines and some saturated pyrimidines is NEIL1, a mammalian homolog to Escherichia coli endonuclease VIII. To investigate the organismal consequences of a deficiency in NEIL1, a knockout mouse model was created. In the absence of exogenous oxidative stress, neil1 knockout (neil1 ؊/؊ ) and heterozygotic (neil1 ؉/؊ ) mice develop severe obesity, dyslipidemia, and fatty liver disease and also have a tendency to develop hyperinsulinemia. In humans, this combination of clinical manifestations, including hypertension, is known as the metabolic syndrome and is estimated to affect >40 million people in the United States. Additionally, mitochondrial DNA from neil1 ؊/؊ mice show increased levels of steady-state DNA damage and deletions relative to wild-type controls. These data suggest an important role for NEIL1 in the prevention of the diseases associated with the metabolic syndrome.DNA repair ͉ fatty liver disease ͉ mitochondria ͉ obesity ͉ oxidative stress A fter exposure to reactive oxygen species (ROS), the major purine lesions are 8-oxoguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, and 4,6-diamino-5-formamidopyrimidine (1-5). To reverse the potentially deleterious effects of oxidative DNA base lesions, cells primarily use the base excision repair (BER) pathway to restore the DNA to its undamaged state (6). The BER pathway is initiated by lesion-specific DNA glycosylases that catalyze bond scission and release the damaged base from the deoxyribose sugar.Unlike nucleotide excision repair, which functions only on nuclear DNA, the BER pathway is operative on both nuclear DNA and mitochondrial DNA (mtDNA). Although BER in the mitochondria repairs normal endogenous oxidant-induced DNA damage, expression of mitochondrially targeted DNA glycosylases that are specific for the repair of oxidatively induced DNA lesions leads to enhanced repair and increased survival after ROS challenge (7-10). These data emphasize that maintenance of the mitochondrial genome is a delicate balance of mtDNA copy number and BER capacity.To initiate repair of oxidative lesions, mammalian cells primarily use the products of the ogg1, nth1, neil1, and neil2 genes (11). These corresponding proteins have somewhat overlapping substrate specificities that may explain, at least partially, the absence of obvious phenotypes in ogg1-and nth1-null mice. NEIL1 has a strong sub...

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Section: Discussionmentioning

confidence: 62%

“…Recently, Das et al (21) demonstrated that neil1 mRNA levels are elevated Ϸ3-fold after ROS exposure. Additionally, NEIL1 was shown to localize in both the nucleus and mitochondria (22), suggesting that this enzyme is involved in the overall maintenance of genomic stability.…”

mentioning

confidence: 99%

The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase

Vartanian

Lowell

Minko

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

224

221

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“…The primary substrates recognized by OGG1 include 8-oxoguanine (8-oxoG), the most commonly formed oxidative DNA lesion, and the formamidopyrimidine derivative of guanine (FapyG). Extracts from mice lacking OGG1 have consistently demonstrated increased accumulation of these lesions [Minowa et al, 2000;Nishimura, 2001;Hu et al, 2005]. However, as discussed below, the relationship between the increased number of lesions and pathological states is not always straightforward.…”

Section: Ogg1mentioning

confidence: 99%

Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

Sampath

2014

Environ and Mol Mutagen

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Cellular components, including nucleic acids, are subject to oxidative damage. If left unrepaired, this damage can lead to multiple adverse cellular outcomes, including increased mutagenesis and cell death. The major pathway for repair of oxidative base lesions is the base excision repair pathway, catalyzed by DNA glycosylases with overlapping but distinct substrate specificities. To understand the role of these glycosylases in the initiation and progression of disease, several transgenic mouse models have been generated to carry a targeted deletion or overexpression of one or more glycosylases. This review summarizes some of the major findings from transgenic animal models of altered DNA glycosylase expression, especially as they relate to pathologies ranging from metabolic disease and cancer to inflammation and neuronal health. Environ. Mol. Mutagen. 55:689-703, 2014. V C 2014 Wiley Periodicals, Inc.

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“…A role for BER in the repair of AFB 1 -Fapy-dG in human cells has not been previously investigated. The human DNA glycosylase that is predominately responsible for the initiation of BER of Fapy adducts is hNEIL1, with substrates including the secondary oxidation products of 8-oxoG, Fapy-dA, Fapy-dG, methyl-Fapy-dG, and a subset of oxidized pyrimidines (22)(23)(24)(25)(26)(27)(28)(29)(30). In addition, this enzyme exhibits distinct structural preference for repairing lesions that are located within DNA bubble structures, modeling DNA intermediates formed during transcription and replication (29).…”

Section: Significancementioning

confidence: 99%

NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice

Vartanian

Minko

Chawanthayatham

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

109

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Global distribution of hepatocellular carcinomas (HCCs) is dominated by its incidence in developing countries, accounting for >700,000 estimated deaths per year, with dietary exposures to aflatoxin (AFB 1 ) and subsequent DNA adduct formation being a significant driver. Genetic variants that increase individual susceptibility to AFB 1 -induced HCCs are poorly understood. Herein, it is shown that the DNA base excision repair (BER) enzyme, DNA glycosylase NEIL1, efficiently recognizes and excises the highly mutagenic imidazole ring-opened AFB 1 -deoxyguanosine adduct (AFB 1 -Fapy-dG). Consistent with this in vitro result, newborn mice injected with AFB 1 show significant increases in the levels of AFB 1 -Fapy-dG in Neil1 −/− vs. wild-type liver DNA. Further, Neil1 −/− mice are highly susceptible to AFB 1 -induced HCCs relative to WT controls, with both the frequency and average size of hepatocellular carcinomas being elevated in Neil1 −/− . The magnitude of this effect in Neil1 −/− mice is greater than that previously measured in Xeroderma pigmentosum complementation group A (XPA) mice that are deficient in nucleotide excision repair (NER). Given that several human polymorphic variants of NEIL1 are catalytically inactive for their DNA glycosylase activity, these deficiencies may increase susceptibility to AFB 1 -associated HCCs.aflatoxin | base excision repair | ring-fragmented purines | liver cancer | environmental toxicant L iver cancers pose an international public health concern as the second leading cause of cancer-related deaths worldwide, with >700,000 estimated deaths per year (1-3). This mortality approaches its annual incidence throughout the world, highlighting the need for development of effective treatments and early diagnostic tools. HCCs represent the major histological subtype among liver cancers. The global distribution of HCCs is dominated by its incidence in developing countries, especially in eastern Asia and Africa, where two major chronic etiological factors drive this disease: (i) routine dietary exposures to grains and nuts that are contaminated with molds, Aspergillus flavus and Aspergillus parasiticus, which produce aflatoxins, and (ii) extremely high rates of hepatitis B (HBV) and C viral infections. In geographical regions of China where aflatoxin contamination of human food products is highest, there is a large shift in not only the age of onset of HCCs, but also in the incidence rate. Within Qidong, a significant number of HCCs occur in males beginning in their early 20s, with the frequency of HCCs peaking between the ages of 40 and 50 (4). These data are in contrast to HCC frequencies in portions of China, such as Beijing, where aflatoxin exposures are minimal. The kinetics of HCC formation in aflatoxin-affected areas are similar to that observed in early onset breast and ovarian cancers in women who are carriers (heterozygotic) for inactivating mutations in BRCA1 or 2.Although there are several different aflatoxin structures, AFB 1 has been demonstrated to be the most potent hepatoc...

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Repair of Formamidopyrimidines in DNA Involves Different Glycosylases

Cited by 181 publications

References 41 publications

The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase

The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase

Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice

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